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New Window Opens on the Secret Life of Microbes: Scientists Develop First Microbial Profiles of Ecosystems
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BBA - Reviews on Cancer (v.1805, #1)
The forkhead factor FOXL2: A novel tumor suppressor? by Bérénice A. Benayoun; Nicolas Kalfa; Charles Sultan; Reiner A. Veitia (pp. 1-5).
FOXL2 is a gene encoding a forkhead transcription factor, whose germline mutations are responsible for the blepharophimosis ptosis epicanthus inversus syndrome. We have previously shown that expression levels of FOXL2 in a series of juvenile ovarian granulosa cell tumors (OGCTs) were markedly reduced. More recently, a whole-transcriptome ‘next-generation’ sequencing study has identified the somatic mutation p.Cys134Trp as recurring in adult OGCTs. This mutation may thus provide the tumor with either a striking proliferative potential or increased survival abilities. These studies of FOXL2 in OGCTs suggest that it may act as a tumor suppressor gene. This is in line with the fact that other forkhead transcription factors have already been involved in the etiology of cancer. Indeed, an in-depth review of existing data on FOXL2 reveals that its target genes and molecular partners can often be linked to cancer progression.
Keywords: FOXL2; Cancer; Ovary; Granulosa cell; Tumor suppressor
Modulation of apoptosis by early human papillomavirus proteins in cervical cancer by A. Lagunas-Martínez; V. Madrid-Marina; P. Gariglio ⁎ (pp. 6-16).
Cervical cancer (CC) constitutes a major women health problem. Clinical, molecular, and epidemiological investigations have identified persistent infection with high risk human papillomavirus (HR-HPV) as the major cause of CC. HR-HPVs lead to development of cervical carcinoma, predominantly through the action of E5, E6 and E7 viral oncoproteins. After HR-HPV infection, viral proteins employ strategies to modulate apoptosis. The E2 viral protein induces apoptosis in both normal and HPV-transformed cells through activation of caspase-8. The E5 protein can impair CD95L- and TRAIL-mediated apoptosis, which suggests that it may prevent apoptosis at early stages of viral infection. E6 inhibits apoptosis through the proteolytic inactivation of pro-apoptotic proteins such as p53, FADD, or procaspase-8, employing the ubiquitin proteasome pathway, or through interactions with proteins that form the death-inducing signaling complex (DISC) such as TNF-R1. On the other hand, E7 oncoprotein expressing cells are usually predisposed to undergo apoptosis. Useful targets for therapeutic strategies would interfere with expression or function of HR-HPV proteins to eliminate cells that express viral oncoproteins. In this review, we summarize the available data on the interaction of early HPV proteins with cellular factors that promote cell death, and the functional consequences of these interactions on apoptosis.
Keywords: HPV; E6; E7; Apoptosis; TNF-α; CD95
Regulation of osteoprotegerin pro- or anti-tumoral activity by bone tumor microenvironment by F. Lamoureux; G. Moriceau; G. Picarda; J. Rousseau; V. Trichet; F. Rédini (pp. 17-24).
Tumor development in bone is often associated with fractures, bone loss and bone pain, and improvement is still needed in therapeutic approaches. Bone tumors are related to the existence of a vicious cycle between bone resorption and tumor proliferation in which the molecular triad osteoprotegerin (OPG)/receptor activator of NF-kappaB (RANK)/RANK ligand (RANKL) plays a pivotal role. RANKL, a member of the TNF superfamily, is one of the main inducers of bone resorption. Its soluble receptor OPG represents a promising therapeutic candidate as it prevents bone lesions and inhibits associated tumor growth. However, its therapeutic use in bone tumors remains controversial due to its ability to bind and inhibit another member of the TNF superfamily, TNF related apoptosis inducing ligand (TRAIL), which is a potent inducer of tumor cell apoptosis. Through its heparin binding domain, OPG is also able to bind proteoglycans present in the bone matrix. This paper is an overview of the involvement of the micro-environment, as represented by the balance of RANKL/TRAIL and the presence of proteoglycans in the regulation of OPG biological activity in bone tumors.
Keywords: Bone tumor; Bone resorption; OPG; RANKL; TRAIL; Proteoglycan
Cell-penetrating peptides: Application in vaccine delivery by Nicole A. Brooks; Dodie S. Pouniotis; Choon-Kit Tang; Vasso Apostolopoulos; Geoffrey A. Pietersz (pp. 25-34).
Recent years have seen a surge in interest in cell-penetrating peptides (CPP) as an efficient means for delivering therapeutic targets into cellular compartments. The cell membrane is impermeable to hydrophilic substances yet linking to CPP can facilitate delivery into cells. Thus the unique translocatory property of CPP ensures they remain an attractive carrier, with the capacity to deliver cargoes in an efficient manner having applications in drug delivery, gene transfer and DNA vaccination. Fundamental for an effective vaccine is the delivery of antigen epitopes to antigen-presenting cells, ensuing processing and presentation and induction of an immune response. Vaccination with proteins or synthetic peptides incorporating CTL epitopes have proven limited due to the failure for exogenous antigens to be presented efficiently to T cells. Linking of antigens to CPP overcomes such obstacles by facilitating cellular uptake, processing and presentation of exogenous antigen for the induction of potent immune responses. This review will encompass the various strategies for the delivery of whole proteins, T cell epitopes and preclinical studies utilizing CPP for cancer vaccines.
Keywords: Cell penetrating peptide; Cancer vaccine; Penetratin; Antigen presentation; Vaccine delivery
Telomerase in cancer immunotherapy by Jun-Ping Liu; Weisan Chen; Anthony P. Schwarer; He Li (pp. 35-42).
Telomerase is a common hallmark of cancer. Recent studies have shown promising developments in anti-telomerase cancer immunotherapy, using human telomerase reverse transcriptase (hTERT) as a tumor antigen. Vaccination, using hTERT peptides or adoptive transfer of hTERT-specific cytotoxic T lymphocytes, induces augmented tumor regression. CD8+ cytotoxic T lymphocytes, against various hTERT peptides, lyse hTERT-expressing tumor cells from multiple tissue origins. CD4+ helper T lymphocytes are also activated by peptides derived from hTERT. This article reviews the current and potential future applications of various hTERT peptide antigens as candidates for cancer vaccines, and explores the experimental challenges that needed to be faced to develop telomerase-based tumor vaccines to treat human cancer.
Keywords: Tumor-associated antigen; Telomerase; hTERT; T cell; Cancer immunotherapy
A new generation of proto-oncogenes: Cold-inducible RNA binding proteins by M.E. LLeonart (pp. 43-52).
This review focuses on the roles of two major cold-inducible RNA binding proteins known in human cells: CIRP and RBM3. Both proteins were discovered when they were shown to be induced after exposure to a moderate cold-shock and other cellular stresses such as UV radiation and hypoxia. Initially, it was suggested that these proteins have a suppressive rather stimulatory effect on proliferation; however, proliferative and/or proto-oncogenic functions have recently been assigned to CIRP and RBM3. In a high throughput genetic screen, we recently identified CIRP as an immortalized gene in murine primary cells. On the other hand, the role of RBM3 in transformation has already been demonstrated. Interestingly, both CIRP and RBM3 have been found to be up-regulated in human tumors. This article highlights the roles of CIRP and RBM3 in tumorigenesis, and proposes a model by which CIRP might contribute to senescence bypass by counteracting the deleterious effects of oxidative damage.
Keywords: CIRP; RBM3; Senescence; Immortalization; Proliferation; Cancer
Immunogenic cell death, DAMPs and anticancer therapeutics: An emerging amalgamation by Abhishek D. Garg; Dominika Nowis; Jakub Golab; Peter Vandenabeele; Dmitri V. Krysko; Patrizia Agostinis (pp. 53-71).
Immunogenic profile of certain cancer cell death mechanisms has been transmuted by research published over a period of last few years and this change has been so drastic that a new (sub)class of apoptotic cancer cell death, redefined as ‘immunogenic apoptosis’ has started taking shape. In fact, it has been shown that this chemotherapeutic agent-specific immunogenic cancer cell death modality has the capabilities to induce ‘anticancer vaccine effect’, in vivo. These new trends have given an opportunity to combine tumour cell kill and antitumour immunity within a single paradigm, a sort of ‘holy grail’ of anticancer therapeutics. At the molecular level, it has been shown that the immunological silhouette of these cell death pathways is defined by a set of molecules called ‘damage-associated molecular patterns (DAMPs)’. Various intracellular molecules like calreticulin (CRT), heat-shock proteins (HSPs), high-mobility group box-1 (HMGB1) protein, have been shown to be DAMPs exposed/secreted in a stress agent/factor-and cell death-specific manner. These discoveries have motivated further research into discovery of new DAMPs, new pathways for their exposure/secretion, search for new agents capable of inducing immunogenic cell death and urge to solve currently present problems with this paradigm. We anticipate that this emerging amalgamation of DAMPs, immunogenic cell death and anticancer therapeutics may be the key towards squelching cancer-related mortalities, in near future.
Keywords: Abbreviations; APCs; Antigen-presenting Cells; ATP; Adenosine Triphosphate; CD; Cluster of Differentiation; CRT; Calreticulin; DAMP; Damage-associated Molecular Patterns; DC/DCs; Dendritic cell(s); DT-EGF; Epidermal Growth Factor Receptor-targeted Diphtheria Toxin; eIF2α; Eukaryotic Initiation Factor 2α; ER; Endoplasmic Reticulum; HMGB1; High-Mobility Group Box-1; HSP; Heat Shock Protein(s); IFN; Interferon; IL; Interleukin; LPS; Lipopolysaccharide; MAPK; Mitogen-activated Protein Kinase; MHC; Major Histocompatibility Complex; NFκB; Nuclear Factor kappa-light-chain-enhancer of activated B cells; NK cells; Natural Killer Cells; PAMP; Pathogen-associated Molecular Patterns; PDT; Photodynamic Therapy; PERK; PKR-like ER kinase; PKR; Protein kinase R; PS; Phosphatidylserine; ROS; Reactive Oxygen Species; TAA; Tumour-associated Antigen(s); TGF; Transforming Growth Factor; TLR; Toll-like Receptor(s); TNF; Tumour Necrosis Factor; UPR; Unfolded Protein Response; UV; Ultra-violet (rays)Immunogenic apoptosis; Necrosis; Autophagic cell death; Cancer; DAMPs; Calreticulin; Anticancer therapeutics
MicroRNAs: Oncogenes, tumor suppressors or master regulators of cancer heterogeneity? by P. Mathijs Voorhoeve (pp. 72-86).
The realization that microRNAs are intimately linked to cancer pathogenesis has spawned an explosion of research activity in recent years. Their presence is not merely predictive of tumor origin and behavior, they are causally linked to the emergence and development of cancer by acting as oncogenes or tumor suppressors. The understanding of the functional consequences of altered microRNA expression in cancer is progressing rapidly, even though the prediction of microRNA targets is still a hit and miss process. MicroRNAs may not act primarily by strongly reducing the expression of a few prominent cancer-regulatory genes, but by influencing the properties of the network of which these regulators are a central part. By coordinately regulating many genes, microRNAs are exquisitely suited to act as stabilizers of networks and to prevent extreme variations in phenotype due to intrinsic and extrinsic disturbances. Many advanced tumors show defects in microRNA expression and processing, which could increase phenotypic variability within tumors. This allows small subsets of cells with altered characteristics to emerge, which can have grave consequences as typically a small fraction of tumor cells is responsible for metastasis and treatment resistance, and ultimately treatment failure. Investigating microRNAs from the perspective of master regulators of network stability in cancer calls for new experimental approaches and may help to understand causes of cancer heterogeneity and disease progression.
Keywords: microRNA; Cancer; Oncogene; Tumor suppressor; Robustness; Heterogeneity
MicroRNAs in the tumor endothelium: Novel controls on the angioregulatory switchboard by Roy Heusschen; Matthijs van Gink; Arjan W. Griffioen; Victor L. Thijssen (pp. 87-96).
Tumor angiogenesis facilitates tumor metastasis and allows malignant tissues to grow beyond a diffusion limited size. It is a complex process that requires endothelial cells to execute specific steps during different phases. miRNAs are small non-coding RNAs that act as molecular switches to redirect the expression profile of a cell. Evidence is emerging that miRNAs are important players in endothelial cell biology and tumor angiogenesis. In this review we summarize the available data of miRNA expression in the endothelium. In addition, we describe the current knowledge regarding the function of miRNAs in endothelial cell biology. Finally, we discuss the potential applications of miRNA based treatment strategies in angiostatic cancer therapy.
Keywords: Cancer; Angiogenesis; miRNA; Endothelial cell
Targeted drug delivery in pancreatic cancer by Xianjun Yu; Yuqing Zhang; Changyi Chen; Qizhi Yao; Min Li (pp. 97-104).
Effective drug delivery in pancreatic cancer treatment remains a major challenge. Because of the high resistance to chemo and radiation therapy, the overall survival rate for pancreatic cancer is extremely low. Recent advances in drug delivery systems hold great promise for improving cancer therapy. Using liposomes, nanoparticles, and carbon nanotubes to deliver cancer drugs and other therapeutic agents such as siRNA, suicide gene, oncolytic virus, small molecule inhibitor, and antibody has been a success in recent preclinical trials. However, how to improve the specificity and stability of the delivered drug using ligand or antibody directed delivery represent a major problem. Therefore, developing novel, specific, tumor-targeted drug delivery systems is urgently needed for this terrible disease. This review summarizes the current progress on targeted drug delivery in pancreatic cancer and provides important information on potential therapeutic targets for pancreatic cancer treatment.
Keywords: Targeted drug delivery; Pancreatic cancer
Tumor heterogeneity: Causes and consequences by Andriy Marusyk; Kornelia Polyak (pp. 105-117).
With rare exceptions, spontaneous tumors originate from a single cell. Yet, at the time of clinical diagnosis, the majority of human tumors display startling heterogeneity in many morphological and physiological features, such as expression of cell surface receptors, proliferative and angiogenic potential. To a substantial extent, this heterogeneity might be attributed to morphological and epigenetic plasticity, but there is also strong evidence for the co-existence of genetically divergent tumor cell clones within tumors. In this perspective, we summarize the sources of intra-tumor phenotypic heterogeneity with emphasis on genetic heterogeneity. We review experimental evidence for the existence of both intra-tumor clonal heterogeneity as well as frequent evolutionary divergence between primary tumors and metastatic outgrowths. Furthermore, we discuss potential biological and clinical implications of intra-tumor clonal heterogeneity.
Keywords: Diversity; Selection; Evolution